1. Field of the Invention
The present invention relates generally to botanical materials and methods for making such materials in medicinally useful and pharmaceutically acceptable forms. More particularly, the present invention relates to the use of compositional and activity fingerprints in the processing of botanical materials to produce drugs which qualify as pharmaceutical grade compositions which are suitable for use in clinical settings to treat disease.
2. Description of Related Art
Plants have been, and continue to be, the source of a wide variety of medicinal compounds. For centuries, various forms of botanically derived materials have been used to treat countless different ailments. The botanical materials have typically been in the form of powders made from of one or more plants or plant parts or extracts derived from whole plants or selected plant parts. These powders and extracts are for the most part complex mixtures of both biologically active and biologically inactive compounds.
Although plant powders and extracts have been used widely for medicinal purposes, there a number of problems associated with the use of such medicaments. For example, the complex and unknown chemical nature of the botanical materials makes it difficult, if not impossible, to use the botanical materials in any type of controlled and predictable manner. The potential variations in the chemical composition of different batches of material obtained from different plant harvests makes such materials unsuitable for use in clinical situations.
On a positive note, the complex groupings of bioactive ingredients typically found in botanical materials presents the potential for synergistic bioactivity profiles. However, these potential increases in medicinal effectiveness are not predictable due to the unknown nature of these complex materials.
The above problems associated with the inherent chemical complexity of botanical medicaments has resulted in a great deal of effort being directed to the separation and isolation of the biologically active ingredients from numerous medicinally important botanical materials. This area of endeavor has expanded rapidly in conjunction with the many improvements in chemical separation and analysis technology. Once isolated and purified, the various active ingredients are used in clinical settings to establish the medicinal effectiveness of the specific ingredient. Separation and purification of individual ingredients from botanical materials is the cornerstone of this type of drug development procedure. Once purified, the suspected active ingredient is typically mixed with a pharmaceutically acceptable carrier and subjected to further studies in laboratory animals and eventual clinical trials in humans. Upon proof of clinical efficacy, these types of drugs are considered to be pharmaceutical grade because they contain a single or at most small number of well-characterized compounds which are present in known quantities.
Pharmaceutical grade drugs are advantageous in that they allow careful tracking of the effects of individual compounds in treatment protocols. Further, the dosage of the drug can be carefully controlled to provide relatively predictable medicinal action. A disadvantage of the relative purity of such pharmaceutical grade drugs is that the potential for complex and synergistic biological activity provided by naturally occurring plant extracts is reduced because of the isolation of the drug from its natural environment. The potential benefit provided by such synergistic activity is believed by many industry experts to be outweighed by the clinical risks associated with the use of complex plant extract mixtures which are not well characterized or controlled and whose use in a clinical setting is unpredictable.
Although isolation and purification of single compounds from plant materials has been a popular form of drug research and development, there also has been interest in studying complex botanical extracts to characterize their medicinal qualities. For example, as discussed below, mistletoe extracts have been studied in some detail.
Mistletoe belongs to the genus Viscum (family, Loranthaceae) which includes a variety of semiparasitic plants found all over the world. Mistletoe is a parasite which grows on a variety of deciduous trees including apple, cherry, oak, ash hawthorn, lime and acorn. Mistletoe and extracts of mistletoe have been used for centuries in a wide variety of therapeutic settings. The effectiveness of mistletoe as a remedy for treating a multitude of ailments has been the subject of a great deal of folklore, superstitions and mystical accounts. Although many of the early uses for mistletoe may have been based more on fantasy than on fact, the reputation of mistletoe as a powerful elixir is well deserved because this parasitic plant contains a rather large variety of complex and pharmacologically potent ingredients.
Beginning in the early 1900""s, mistletoe and the pharmacological properties of extracts from mistletoe have been subjected to a more rigorous scientific investigation. In particular, mistletoe extracts have been suggested for use in treating a variety of specific diseases including cardiovascular illnesses, especially hypertension and arteriosclerosis; cancer and arthrosis. Fermented mistletoe extracts marketed under the tradenames ISCADOR(copyright), HELIXOR(copyright) and PLENOSOL(copyright) have been proposed for use in treating a number of specific diseases. ISCADOR(copyright) and HELIXOR(copyright) have been injected subcutaneously while PLENOSOL(copyright) has been administered both intracutaneously and intravenously. These three commercially available preparations are derived from mistletoe found in Europe, Viscum album L. 
Since 1980, the investigation of mistletoe has increased due to its immunomodulatory properties and potential usefulness in treating HIV and cancer. See International Journal of Cancer Research Treatmentxe2x80x94ONCOLOGYxe2x80x94Vol. 43, Supplement 1, 1986. A major problem facing mistletoe investigators has been the analysis, identification and standardization of the pharmacologically active ingredients in mistletoe and extracts thereof. This problem is exacerbated by the fact that the numerous complex ingredients which are found in mistletoe extracts vary widely in type and amount depending upon the species of mistletoe, the location where the plant is grown, the time of year when the plant is harvested, the particular host tree, the extraction procedure used and a number of other factors.
The principal classes of ingredients in mistletoe which have been found to provide pharmacological activity include lectins, phenylpropans, viscotoxins, alkaloids, flavonoids, lignans, amines, phenyl carboxylic acids and polysaccharides. Although the general classes of pharmacologically important compounds which are generally present in mistletoe have been identified, investigators have not had a great deal of success with respect to standardizing the multitude of available extracts to establish if one or more ingredients are responsible for the observed bioactivity and whether the specific ingredients act together or may be effective individually. The extremely diverse nature of mistletoe extracts and the inherent variability in extract compositions makes it difficult to use the extracts to conduct clinical investigations.
The preceding discussion regarding mistletoe is exemplary of the state of the art with respect to the plant materials which have been studied in detail. Many other complex plant materials and extracts exist which have potent, but relatively unpredictable, medicinal properties. These manufactured materials are, for the most part, useless in a clinical setting because of the inherent risks involved with treating patients with poorly characterized materials which have no established batch consistency and which may differ widely in composition. Accordingly, there is a need to provide methods for standardizing such complex materials so that they may be used more effectively in clinical research and patient treatments.
In accordance with the present invention, a method is provided for making pharmaceutical grade botanical drugs. The term xe2x80x9cpharmaceutical gradexe2x80x9d when used in this specification means that certain specified biologically active and/or inactive components in the botanical drug must be within certain specified absolute and/or relative concentration limits and/or that the components must exhibit certain activity levels as measured by a given bioactivity assay. The pharmaceutical grade botanical drugs made by the method of the present invention are particularly well-suited for use in clinical studies and treatment of patients in general. The method insures that the drug being used as the basis for a particular treatment protocol will be effective for its intended purpose.
The method of the present invention involves processing a biological material to produce a composition which qualifies as a pharmaceutical grade drug by meeting certain requirements with respect to the quantity of specific ingredients (i.e. quantitative fingerprint) and the biological activity of the material with respect to one or more biological assays (i.e. biological fingerprint). Initially, a sample of the botanical material of interest is obtained. The material, if necessary, is processed to form an extract or other composition which is intended for use as a drug. The processed material may include a plurality of active ingredients which exhibit a given biological activity and plurality of inactive ingredients which do not directly exhibit the biological activity of interest. An aliquot is removed from the botanical material and subjected to quality assurance or standardization assay. The assay involves separating the aliquot of processed material into a plurality of marker fractions wherein each of the marker fractions includes one of the active ingredients or one of the inactive ingredients. The amount of active ingredient or inactive ingredient in each of the marker fractions is determined in order to provide a quantitative fingerprint of the aliquot. The degree of biological activity for each of the marker fractions is also determined to provide a biological activity fingerprint for the aliquot. The quantitative and biological activity fingerprints of the aliquot are then compared to corresponding fingerprints which have been established for a pharmaceutical grade drug. If the fingerprints of the processed botanical material match the standard fingerprints, then the material is identified as a pharmaceutical grade botanical drug. If not, then the material is modified so as to provide a match with the standard fingerprints.
The method of the present invention is well-suited for use in preparing a wide variety of botanical drugs which can be used in clinical settings for research and general patient treatment. The present invention provides the ability to closely control the quality, dosing and clinical effectiveness of botanical extracts and other material. One aspect of the present invention involves the establishment of the compositional and/or bioactivity fingerprint standards for various botanical materials. Once established, the fingerprint standards are used in drug production procedures to insure that the botanical extracts meet pharmaceutical grade requirements. Specific quantitative and biological fingerprints are presented which have been established for a number of botanical materials as a further aspect of the invention. These fingerprints are useful for determining if a particular botanical material meets levels of pharmacological activity and composition requirements for a particular treatment regimen. Such a determination is important to insure that clinical studies and patient treatment with the botanical materials are based on consistent and verifiable extract composition parameters.
The above discussed and many other features and attendant advantages of the present invention will become better understood by reference to the following detailed description when taken in conjunction with the accompanying drawings.